The present invention relates to pharmaceutical compositions and methods for the treatment of cancer.
Following surgical removal or radiation therapy for the removal or reduction of hard and soft tissue tumors, patients are faced with the possibility of persistent tumor cells, metastasis and tumor reoccurrence. In the case of bone tumors, patients face the additional problem of poor mechanical integrity of the bone. Cancer patients typically receive postoperative chemotherapy to reduce the chances of tumor reoccurrence and metastasis. Chemotherapy also is used for the treatment of inoperable tumors. Systemically delivered anticancer drugs often produce severe side effects, such as liver toxicity, cardiotoxicity, hair and weight loss. Therapies often are discontinued or otherwise limited due to these adverse side effects.
While the effectiveness of chemotherapy has improved tremendously, the side effects associated with its administration remain a significant factor in patient mortality. Therefore, an important consideration when treating bone tumors and soft-tissue tumors with chemotherapeutic agents is maintaining a long-acting, yet highly effective concentration of the anticancer agent at the local site of the tumor while minimizing the often toxic systemic side effects.
MacroMed reports the use of a biodegradable polymer having reverse thermal gelation properties for intra-tumoral injections. Under the tradename OncoGel™, the poly(lactide-co-glycolide)-based polymer is deliverable through a small-gauge (25) needle and localized delivery is reported. See, U.S. Pat. No. 5,702,717 for further information on the polymeric material.
Hydroxyapatite is a major mineral in bone and teeth. It demonstrates excellent biocompatibility with bony tissue and has been used in the orthopedic industry as bone-filling material. Anticancer agents such as adriamycin, cis-platin and methotrexate have been incorporated into porous hydroxyapatite beads and blocks, and sustained release of the agents have been demonstrated. Administration of the drug-loaded blocks to a tumor site in a cancer rat model resulted in increased life span and reduction in body weight loss. See, Yamamura et al. Jpn. J. Pharmacol. 65:289 (1994); Yamamura et al. Jpn. J. Pharmacol. 66:433 (1994); and Uchida et al. J. Orthop. Res. 10(3):440 (1992).
However, hydroxyapatite ceramics typically are dense, highly crystalline materials, and as such, are poorly resorbable. Porosity must be engineered into the material to permit drug uptake during drug loading and drug release at the tumor site. Engineering of the hydroxyapatite block for a particular drug release profile is difficult and not easily reproducible. An additional limitation of use of a hydroxyapatite solid block or bead is that it requires surgical implantation.
Calcium phosphate cements are compositions having one or more dry components and a liquid which combine to form a material that is capable of setting into a solid calcium phosphate product. Materials that set into solid calcium phosphate mineral products are of particular interest as such products can closely resemble the mineral phase of natural bone, are potentially remodelable, and are biocompatible.
Patents of interest describing calcium phosphate cements include: U.S. Pat. No. 4,684,673 to Adachi et al.; U.S. Pat. No. 5,037,639 to tung et al., U.S. Pat. Nos. 5,683,461, 5,676,976 and 5,650,176 to Lee et al; U.S. Pat. Nos. 4,108,690, 5,968,253 to Posner et al. and U.S. Pat. No. 5,508,342 to Antonucci et al, as well as U.S. Pat. Nos. 4,880,610, 5,047,031, 5,129,905, 5,336,264, 5,053,212, 5,178,845, and 5,580,623 to Constantz et al.; U.S. Pat. Nos. 5,569,442 and 5,571,493 to Fulmer et al.; and U.S. Pat. Nos. 5,496,399; 5,683,667; 5,683,496; and 5,697,981 to Ison et al. Also of interest are WO 96/36562 and WO 97/17285.
Constantz et al., “Skeletal Repair by in Situ Formation of the Mineral Phase of Bone,” Science (Mar. 24, 1995) 267: 1796-1798, describes a calcium phosphate cement comprising α-tricalcium phosphate, monocalcium phosphate monohydrate (MCPM), and CaCO3. Also of interest is Otsuka et al. “A Novel Skeletal Drug Delivery System Using Self-Setting Calcium Phosphate Cement. 9: Effects of the Mixing Solution Volume on Anticancer Drug Release from Homogeneous Drug-loaded Cement” J. Pharm. Sci. 84(6):733 (June 1995), which describes a calcium phosphate cement made up of tetraclacium phosphate (TTCP) and dicalcium diphosphate (DCPD) and incorporating the anticancer agent 6-mercaptopurine (6-MP). The addition of 6-MP was reported not to interfere with the setting properties of the cement; however, the drug release profile form the cement was not acceptable, presumably due to crystallization of the calcium phosphate cement with time. The effectiveness of cement as a delivery system was not established, as only model in vitro release studies were reported.
A number of these calcium phosphate cements suffer from one or more drawbacks, such as low resorbability, rapid set time, poor flow characteristics and inability to provide controlled release of an active agent. None of the calcium phosphate cements report setting times and material flow characteristics which are amenable to injection or cannulation.
Thus, there is a need for an anticancer agent delivery system that combines desirable delivery characteristics (e.g. resorbability, controlled release, biocompatibility) in conjunction with the ability to be injectable, and thus able to administer the therapeutic mixture by syringe or cannula.
There remains a need for a drug delivery system that slowly releases an anticancer agent exclusively into the tumor.
There remains a further need for a drug delivery system that is easy to administer to the tumor site with minimum trauma to the patient.